PROJECT SUMMARY/ABSTRACT The Environmental Determinants of Diabetes in the Young (TEDDY) study was initiated in 2003 by six clinical centers in the United States and Europe, including ours, to identify infectious agents, dietary factors, or other environmental exposures that may trigger or protect against the development of islet autoimmunity and type 1 diabetes (T1D). Additional long-term scientific goals include assessment of potential gene-environment interactions affecting development of islet autoimmunity or T1D, gaining insight on triggering mechanisms through detailed multi-omics analyses, and sharing collected specimens with broader scientific community for studies of T1D pathogenesis and prevention. A total of 424,788 newborns were screened by HLA-DR,DQ genotyping to identify children at increased risk for T1D and 8,676 enrolled for quarterly follow-up until age 4 and semi-annually thereafter until age 15. Now, 13 years after enrollment began, 5731 (66%) remain actively engaged in the protocol. Our Germany Clinical Center enrolled 593 TEDDY participants. As of 2/28/18, 56 of those have developed persistent confirmed islet autoantibodies and 31 have been diagnosed with T1D. Detailed analyses of biological samples from the entire cohort, along with even more comprehensive multi- omics analyses in selected individuals, will provide a rich dataset to complement the intensive collection of exposure data and highly efficient ascertainment of islet autoimmunity and T1D endpoints in the entire cohort. Specific aims of this renewal application for this multi-center, prospective cohort study for the next 5 years are: 1. Follow the TEDDY cohort of high-risk children for development of islet autoimmunity, diabetes, celiac disease and autoimmune thyroid disease until 15 years of age; collect biological specimens and epidemiological data according to the study protocol. 2. Characterize genetic, epigenetic, transcriptomic, proteomic and metabolomic determinants of islet autoimmunity and T1D in the study participants. 3. Prospectively assess infectious, dietary and other environmental exposures of study participants as triggers of islet autoimmunity, promotors of progression to T1D, or both. A successful study outcome will provide a dataset unprecedented in depth and breadth, to help elucidate specific exposures and mechanisms serving in the etiology and pathogenesis of islet autoimmunity, T1D, and closely related autoimmune diseases. The results will support the development of new strategies to prevent, delay, or reverse the disease.